Factors associated with persistent postsurgical pain after total knee or hip joint replacement: a systematic review and meta-analysis

Abstract Studies have identified demographic, clinical, psychosocial, and perioperative variables associated with persistent pain after a variety of surgeries. This study aimed to perform a systematic review and meta-analysis of factors associated with persistent pain after total knee replacement (TKR) and total hip replacement (THR) surgeries. To meet the inclusion criteria, studies were required to assess variables before or at the time of surgery, include a persistent postsurgical pain (PPSP) outcome measure at least 2 months after a TKR or THR surgery, and include a statistical analysis of the effect of the risk factor(s) on the outcome measure. Outcomes from studies implementing univariate and multivariable statistical models were analyzed separately. Where possible, data from univariate analyses on the same factors were combined in a meta-analysis. Eighty-one studies involving 171,354 patients were included in the review. Because of the heterogeneity of assessment methods, only 44% of the studies allowed meaningful meta-analysis. In meta-analyses, state anxiety (but not trait anxiety) scores and higher depression scores on the Beck Depression Inventory were associated with an increased risk of PPSP after TKR. In the qualitative summary of multivariable analyses, higher preoperative pain scores were associated with PPSP after TKR or THR. This review systematically assessed factors associated with an increased risk of PPSP after TKR and THR and highlights current knowledge gaps that can be addressed by future research.


Introduction
Persistent postsurgical pain (PPSP) is a common sequel of surgical procedures. The prevalence varies for different surgical procedures and in different studies, ranging from a low of 3% to a high of 81%, 90 with a reported incidence of about 20% after bone and joint surgeries. 39 PPSP substantially impairs quality of life, has negative economic consequences, 35 and is a potentially preventable condition. 106 Patients who undergo elective procedures such as total hip or knee replacement, typically expect alleviation of the pain associated with the damaged joint. Although these procedures have a high likelihood of success in relieving pain and restoring function, PPSP is a major factor that negatively affects patient satisfaction with joint replacement surgery outcomes. 72 Therefore, understanding factors predisposing patients to an increased risk of persistent pain is important in attempts to prevent PPSP or minimize its occurrence. The identification of patients at high risk for PPSP will allow allocating perioperative resources for PPSP risk mitigation and may signal a need for enhanced postoperative follow-up and early referral to multidisciplinary evaluation. Several studies been have published on perioperative risk factors associated with PPSP, 120 but it is yet unclear which factors show a consistent association with PPSP. 47,67 Several systematic reviews have been published on psychosocial factors in general 43 or anxiety and catastrophizing specifically 107

as risk factors for PPSP, and individual studies have reported on factors associated with orthopedic surgeries
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Risk of bias assessment
Most validated tools for assessing the ROB in systematic reviews 42 refer to assessing the methodology of randomized controlled trials. Because this study aimed to analyze factors associated with PPSP (from both prospective and retrospective studies), an alternative method for the ROB systematic assessment was applied based on the methodology used in other systematic reviews focusing on the analysis of predicting factors. 53,56,116 Potential sources of bias were evaluated and addressed whether (1) the sample adequately represented the population of interest, (2) the data represented the sample, and (3) the outcome of interest was adequately measured to limit potential bias (Appendix 2, available at http://links.lww.com/ PR9/A184). Other potential serious sources of bias were documented-eg, selective reporting of outcomes, use of nonvalidated scales, or lack or inappropriateness of sample size calculation.

Protocol for data extraction
To address the different study designs, we developed guiding principles for data extraction across all studies (Appendix 3, available at http://links.lww.com/PR9/A184). In brief, all studies which addressed PPSP at or more than 2 months were included, and the follow-up timeframe at or closest to 6 months was obtained in case of multiple follow-ups. Although the cutoff for postsurgical duration of pain has most commonly been set at 2 or 3 months, some patients have a longer rehabilitation period after total knee or hip joint replacement surgeries. 38,55 Thus, to remove the confounder, we decided to set the primary outcome timeframe at around 6 months after surgery in studies with multiple follow-ups. If PPSP was categorized based on a severity scale (numerical rating scale [NRS] or Likert scale), the data were dichotomized to a "no pain to mild pain" group vs a "moderatesevere pain" group, to allow 2 3 2 table formation. In addition, to allow systematic analysis of data, some factors were combined, eg, epidural and spinal anesthesia were merged under neuraxial anesthesia.

Data synthesis and analysis
The data analyses were performed using RStudio version 1.4.1103. 93 For binary factors, 2 3 2 tables were created, and risk ratios were calculated to be used in generating forest plots. For continuous variables (eg, age and body mass index [BMI]), weighted mean differences were used. Only raw univariate data were used for generating forest plots. Values for weighted mean differences were presented as means with standard deviation (SD). Risk Ratio (RR) or odds ratio was presented as risk or odds, with 95% confidence interval (CI). Meta-regression of multivariable data was not possible because each study accounted for different risk factors. Data on risk factors from multivariable analyses were aggregated in a tabulated form to help make qualitative inferences about common contributing factors.

Results
The systematic literature search resulted in a total of 10,851 potential articles. After removing 5,403 duplicate records, a total of 5,448 unique citations were added to the project library. All abstracts of identified studies were reviewed for inclusion criteria, resulting in 231 full-text articles that were considered for full review (see Appendix 1 for full details about literature search strategy and results, available at http://links.lww.com/PR9/ A184). These articles were independently evaluated for inclusion by 2 reviewers (AG and SB/SS), and 81 were included in the final analysis (Fig. 1).
The studies analyzed included total hip and/or knee joint replacement surgeries. The overall study characteristics are outlined in Table 1. The minimum cutoff for determining PPSP in the included studies was 3 months after surgery. 98 The total number of patients across all total hip and/or knee joint replacement surgery studies (n 5 81) was 171,354 with a mean (SD) sample size of 2,115 (14,226), 28 (34.6%) studies involving less than 100 participants. The mean PPSP rate was 16.4%.
Studies investigating PPSP after both total hip and knee joint replacement surgery (n 5 11) included 10,399 participants and reported a mean PPSP incidence of 26.7%. Studies after total hip joint replacement surgery alone (n 5 16) included 9,086 participants and reported a mean PPSP incidence of 16.5%, and those after total knee joint replacement surgery alone (n 5 54) included 151,869 participants and reported a mean PPSP incidence of 15.6%. Overall, 69 of the studies were prospective and 12 were retrospective. A total of 36 studies have provided univariate data to be included in meta-analysis, and 64 studies have reported risk factors in multivariable analyses, from which data were used for qualitative summary (Fig. 1). The studies overall had medium to low ROB ( Table 2). The main category to have significant ROB was a "follow-up rate .75% at the first follow-up" (with 14 studies (17%) with high ROB), incomplete characterization of study dropouts (with 65 studies [80%] having unclear or high ROB).Thirty five of the 81 included studies (43%) had high or unclear bias in one of the categories of pain outcome measurement-either in PPSP definition, its method of assessment or classification, or reporting-and 62 of 81 (76.5%) studies reported sources of funding. Although there is not a good way to assess publication bias related to risk prognostic studies, 105 funnel plots to assess asymmetry among most commonly reported risk factors did not suggest important publication bias (Appendix 4, available at http://links. lww.com/PR9/A184). The demographic factors with data from multiple studies that allowed testing their association with an increased risk of PPSP were age, the proportion of women in the total study population,   and BMI, whereas clinical factors included duration of surgery (in minutes), preoperative factors such as presence of anxiety and depression, knee or hip joint pain, or pain elsewhere in the body. Age (Fig. 2) and sex ( Fig. 3) were not associated with an increased risk of PPSP after TKR or THR (Appendix 5 and Appendix 6 respectively, available at http://links.lww.com/PR9/ A184) studies when analyzed separately. However, younger age (SMD 20.18 years [95% CI 20.30 to 20.06]) (Fig. 4) and female sex (RR 1.13, 95% CI 1.02-1.24) (Appendix 7, available at http:// links.lww.com/PR9/A184) were associated with an increased risk in a small subset of studies reporting on the combined knee and hip replacement surgeries (n 5 2).
Body mass index was not associated with a risk of PPSP in TKR studies (Fig. 5), but higher BMI was associated with higher PPSP occurrence in the subset of studies reporting both hip and knee replacement (SMD 0. 15 7) were associated with an increased risk of PPSP in studies reporting PPSP after total knee joint replacement surgery, but not for depression (Appendix 10, available at http://links.lww.com/PR9/ A184) or anxiety (Appendix 11, available at http://links.lww.com/ PR9/A184) scored in the Hospital Anxiety and Depression Scale.
Other associations tested were duration of surgery (mins) (Appendix 13, available at http://links.lww.com/PR9/A184) and pre-existing pain at other sites of the body (Appendix 14, available at http://links.lww.com/PR9/A184), but these did not reach statistical significance. Table 3 presents a qualitative summary of risk factors that were reported in multivariable analyses in the included studies. Factors are reported as either having a significant association with an increased occurrence of PPSP (red) or no association (yellow). The variables for which the risk factors were adjusted for differ among the studies.

Demographic factors
In multivariable analysis, an increased risk of PPSP was associated with younger age in 4 16

Preoperative factors
Large variability in the incidence of PPSP was found by 2 studies depending on the definition 19 (any pain within the last 4 weeks: NRS .0 vs current pain at the time of the interview NRS .0 vs moderateto-severe pain at the time of the interview: NRS .3) and assessment instrument used 76 (Knee Injury and Osteoarthritis Outcome Score pain subscale vs visual analogue scale) to measure pain. Increased risk of PPSP was associated with higher pre-existing pain intensity in 17 1,13,85,89,97,100,104,27,20,27,28,50,71,74,82,2,58 of 30 studies and with unresolved postoperative pain in the affected knee or hip joint in 12 4,6,108,15,20,36,41,45,48,61,85,49 of 41 studies that tested these variables as independent risk factors.

Pre-existing health conditions
Higher PPSP was observed in patients with comorbidities such as hypertension, diabetes, ischemic heart disease, chronic obstructive pulmonary disease, asthma, and neurological illnesses in 7 studies, 3,30,94,100,69,126,25 and patients with the presence of widespread pain in other parts of the body in 5 studies. 26,70,100,111,123 3.6. Psychological factors Increased risk of PPSP was associated with pre-existing anxiety in 8 13,15,25,36,65,73,89,114 of 20 studies, with pre-existing depression in 7 13,15,25,36,99,111,122 of 20 studies, with preoperative pain catastrophizing in 2 30,65 of 11 studies, and with poorer baseline performance on cognitive flexibility tests in 2 studies 3,112 that tested these variables as independent risk factors.  Forest plot for the association between age and PPSP in total knee joint replacement surgeries analyzed together. *Higher/positive SMD represents the difference in age (in years) between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups. Figure 3. Forest plot for the association between the proportion of women in the study population and PPSP in total knee joint replacement surgeries. *Risk ratio (RR) .1 represents higher, RR ,1 represents lesser, while RR 5 1 represents a similar occurrence of PPSP in women compared with the study population, the horizontal box and whisker plots are the group RRs 695% confidence intervals, and the blue diamond is the combined RR of groups.

Psychophysical assessments
Low preoperative pressure pain detection threshold was associated with PPSP in 1 study, 77 whereas temporal summation of pain (TSP) or conditioned pain modulation (CPM) alone showed no associations, but the association with CPM was seen in male subgroup patients. 10 Increased odds of PPSP were also observed with heat hyperalgesia, 62 preoperatively facilitated TSP, 45 expected pain and TSP, 89 and with preoperative widespread pain sensitization measured using pressure algometry, 125 whereas hypoalgesia after cold pressor stimulation and aerobic exercise assessed preoperatively by cuff algometry was associated with less PPSP. 110

Perioperative interventions
There were no sufficient data to combine perioperative interventions in the meta-analyses. Data from 1 or 2 articles were available on each intervention; therefore, only a qualitative summary is provided below.
In the 4 studies which reported on regional anesthesia in TKR, a reduced incidence of PPSP was reported with continuous femoral nerve block analgesia with standardized rehabilitation therapy in 1 study, 76 whereas analgesic benefit was noticed only for up to 1 month after surgery in 1 study 15 or even for a shorter immediate postoperative period but not 3 or 6 months postsurgery in the other 2. 51,128 There was reduced pain at 3 months after TKR with intrathecal baclofen used as an adjuvant to spinal anaesthesia, 95 with sevoflurane anaesthesia, 127 and with preventive epidural analgesia. 86 Perioperative pregabalin administration reduced the incidence of chronic neuropathic pain in a single study. 17 After THR, a single 600-mg dose of gabapentin given preoperatively or postoperatively neither reduced morphine consumption nor pain scores in the hospital or after 6 months within the context of spinal anesthesia and a robust multimodal analgesia regimen. 21 There was no difference between local infiltration analgesia and intrathecal morphine or femoral nerve block, 51 and no effect of a single spinal dose of ketorolac 115 or perioperative ketamine 88 on PPSP prevention. There was no effect on PPSP from preoperative analgesia and neuraxial anesthesia in a study analyzing THR and TKR together. 36

Discussion
This systematic review and meta-analysis focused on identifying reported factors associated with PPSP risk across a group of hip joint and knee joint replacement surgeries. Overall, 81 studies met the eligibility criteria and were included for further analyses. The studies selected based on inclusion criteria had mostly low or unclear ROB for appropriate representation of the surgical population tested, study design, likelihood of publication bias, and the measurement of pain outcomes. However, based on ROB assessment, important sources of bias and heterogeneity were low follow-up rate and inconsistent characterization of participants who dropped out of studies, as well as inconsistent definition of PPSP, its assessment methods and reporting. The overall mean PPSP rate was 16.4% (16.5% after THR and 15.6% after TKR), which was similar to the previous literature review (9% or more after THR and about 20% after TKR). 59  . Forest plot for the association between age and PPSP in total knee and hip joint replacement surgeries analyzed together. *Higher/positive SMD represents the difference in age (in years) between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups. Figure 5. Forest plot for the association between body mass index (BMI) in kg/m 2 and PPSP in total knee joint replacement surgeries analyzed together. *Higher/ positive SMD represents the difference in BMI units between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups.

Knee joint replacement surgeries
The results of the meta-analyses in knee joint replacement surgeries from 54 studies demonstrated an increased risk of PPSP in individuals with higher state anxiety (but not trait anxiety) scores and higher depression scores (in Beck Depression Inventory). Literature suggests that a bidirectional relationship exists between pain and anxiety or depression, and observations from functional imaging studies suggest that this bidirectional relationship is due in part to shared neural circuitry, particularly related to mechanisms of emotional regulation of pain. 130 The qualitative summary of multivariable analysis from 43 studies pointed out several possible factors associated with PPSP but with limited data and evidence. Presurgical pain intensity was the only factor where more studies reported an independent risk with PPSP compared with studies that did not find such an association. Although factors such as younger age, female sex, higher BMI, high catastrophizing, more severe acute postoperative pain, pre-existing depression, or anxiety were independently associated with PPSP in some studies, there were generally more studies that did not find such independent association. Certain factors were demonstrated in single studies to increase the risk of PPSP. Among these were being a widower; being a housewife; not having higher education; working at a job that requires physical effort; 1 presurgical restricted walking distance; pre-existing knee pain; neuropathic pain; 81 pre-existing chronic pain states; 119 poorer cognitive flexibility; comorbidities such as diabetes mellitus, cancer, and fibromyalgia; 33 revision surgery compared with primary TKA; 79 mechanical complication of prosthesis; 48 and painful postoperative period. 34 Given the paucity of data, future research will be needed to test these associations further.
Interventions such as preoperative exercise and education were suggested to have low-quality to moderate-quality evidence in a recent review, 24 but we did not find any evidence in the included studies to quantify these measures. Perioperative pregabalin administration reduced the incidence of chronic neuropathic pain in 1 study 17 but has been refuted in a meta-analysis. 63 Continuous regional anesthesia provided analgesic benefit for up to 1 month after surgery but did not influence PPSP outcomes at 6 months, 15 and single-injection femoral nerve block did not affect PPSP. 128 Because these findings are based on a limited number of studies, it is impossible to draw robust conclusions on the effectiveness of these perioperative interventions to prevent PPSP.

Hip joint replacement surgeries
The results of the meta-analyses in hip joint replacement surgeries only from 5 studies could not demonstrate any statistically significant results for factors consistently associated with an increased risk of PPSP. The qualitative summary from multivariable analysis results from 10 studies pointed out several possible factors associated with PPSP; however, there is insufficient evidence to conclude these contributing factors because of a small number of studies reporting them. Young age, 91 female sex, 103 higher time spent with pain in the perioperative period, presurgical anxiety or depression, higher BMI, poor Harris Hip Score, 11 presence of loose beads from the prosthesis, pain at other sites of the body, preoperative pain disability, higher cumulative opioid consumption, 52 and high intraoperative nociception were the factors reported to be associated with an increased risk of PPSP in some, but not other studies. The current data on preoperative education of patients undergoing THR are unclear, 32,46,68 and we did not find any conclusive evidence on PPSP prevention with this approach. Perioperative ketamine was associated with a reduction in the risk of PPSP in 1 study 87 but has been refuted in a meta-analysis. 49 A single perioperative dose of gabapentin, 21 spinal ketorolac, local infiltration analgesia, and femoral nerve block did not show a protective effect on the presence of PPSP at 6 months after THR. These findings are based on limited data; therefore, no conclusion can be drawn of effective strategies for preventing PPSP after THR. Figure 6. Forest plot for the association between state anxiety and PPSP in total knee joint replacement surgeries analyzed together. *Higher/positive SMD represents the difference in the state anxiety score between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups. Figure 7. Forest plot for the association between depression scored in the Beck Depression Inventory (0-39) and PPSP in total knee joint replacement surgeries was analyzed together. *Higher/positive SMD represents the difference in depression scored in the Beck Depression Inventory (score range 0-39) units between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups.

Hip and knee joint replacement surgeries
The results of the meta-analyses in studies that combined patients undergoing hip and knee joint replacement surgeries demonstrated an increased risk of PPSP in women and patients with higher BMI, but the number of studies is likely too small to draw any meaningful conclusions. The qualitative summary of multivariable analyses from 11 studies pointed out several possible factors associated with PPSP. Functional severity of joint pathology, higher time spent with pain in the preoperative period, presurgical anxiety or depression, and presence of pain in other areas of the body were associated with higher instances of PPSP, whereas preoperative analgesia and neuraxial anesthesia were associated with less PPSP in 1 study. It has been reported that younger patients are more likely to develop PPSP after orthopedic surgery, 8 but this finding was not consistent across studies. 75 Mechanisms explaining the increased incidence of chronic pain in younger patients are unknown but may relate to a reduction in peripheral nociceptive function and density with increased age. 129 It has been reported that women experience higher pain intensity at a lower level of inflammation after knee surgery compared with men, which has been attributed to central mechanisms of pain perception. 101 Data from the American College of Surgeons National Surgical Quality Improvement Program database has shown that the degree of obesity (high BMI) relates to the of risk of postoperative complications in hip and knee arthroplasty, 92 which is consistent with our findings from the qualitative summary. Several factors, such as employment status, illiteracy, history of hypertension or diabetes, and previous knee or hip replacement surgeries have been reported to be associated with higher PPSP in the literature but did not show association in this combined analysis. 83,84

Assessment of chronic pain
Chronic pain as a subjective lived, and sensory experience presents particular challenges to assessment. 7 This review has identified the following tools used for assessing chronic pain: Oxford Knee Score (joint-specific questionnaire assessing pain severity and interference), Western Ontario and McMaster Universities Osteoarthritis Index, Knee Injury and Osteoarthritis Outcome Score (disease-specific questionnaire assessing pain severity), the Brief Pain Inventory (disease-agnostic questionnaire with a pain severity subscale [4 items] and a pain interference subscale [7 items]), Short-Form McGill Pain questionnaire (disease-agnostic questionnaire assessing sensory and affective qualities of pain), Pain visual analogue scale (unidimensional assessment of pain severity), PainDETECT (a neuropathic pain questionnaire), and Douleur Neuropathique 4 (DN4, a neuropathic pain questionnaire). Because these tools are selected based on study objectives and each measure a somewhat different dimension of pain severity, characteristics, and interference, direct comparison among studies is challenging. It is increasingly recognized that the accurate assessment of patient-reported outcome measures (PROMs) in orthopedic surgery trials and registries is important and ideally should include metrics of quality of life, functioning, disability, and patient satisfaction. 9,66 In both clinical and research settings, the approach to assessing chronic pain after THR or TKR needs to be in-depth and multidimensional to understand the characteristics and impact of this pain. Unfortunately, the heterogeneity in PROM assessment in the included studies did not allow to robustly test the associations between PPSP and PROMs. We could not identify risk factors that are associated with diminished pain-related quality of life after knee and hip joint replacement surgeries. Only 1 study showed diminished quality of life in patients with PPSP compared with those without, 36 while 2 other studies focused on quality of life measures in the context of perioperative anesthesia selection 127 and general longitudinal outcomes of joint replacement surgery. 69

Quantitative sensory testing modalities
Quantitative sensory testing (QST) is a psychophysical approach used to quantify somatosensory function in response to controlled stimuli. 5 The idea of using QST in the preoperative setting to determine an individual's response to painful stimuli is appealing as a possible predictor of a response to a painful surgical procedure. In this review, heat pain threshold such as hyperalgesia was associated with perioperative pain after TKR 62 Figure 8. Forest plot for the association between preoperative numerical rating scale pain score (0-10) and PPSP in total knee joint replacement surgeries analyzed together. *Higher/positive SMD represents the difference in preoperative numerical rating scale pain score (0-10) units between patients who developed PPSP vs those who did not, the horizontal box and whisker plots are the group SMDs 695% confidence intervals, and the blue diamond is the combined SMD of groups. Table 3 Qualitative summary of risk factors for PPSP reported in multivariable analyses in included studies.
(continued on next page) and preoperatively facilitated TSP and CPM assessed using mechanical stimuli or manual cuff stimuli with knee osteoarthritis. 78,80,125 Hypoalgesia after cold pressor stimulation and aerobic exercise assessed preoperatively by cuff algometry was associated with pain relief 6 months after TKR. 110

Potential modifiers
Certain factors such as anxiety, depression, catastrophizing, and BMI are potentially modifiable, and future studies should investigate whether preoperative modification of these factors can mitigate PPSP risk. Cognitive behavior therapy and other holistic approaches may be relevant in this setting. 118 Other risk factors such as age, and sex are not modifiable; however, they may be important to developing risk stratification tools. Intraoperative and perioperative factors such as surgical and anesthesia techniques as well as perioperative care and analgesia plans can be modified to mitigate the risk for PPSP in these patients.

Limitations of our study
It is important to acknowledge the limitations of this review when interpreting the results. First, although we performed a systematic literature search, gray literature as well as abstracts and dissertations were not evaluated, potentially missing some studies. Some full-text articles described data in a format which could not be retrieved for meta-analyses; these data were only included in a qualitative summary. We contacted authors in such situations but were only successful to obtain additional data in a few cases. We included a mix of both retrospective and prospective studies, as well as observational and interventional studies. There are no guidelines how to weigh risk factors based on differences in study design, 23 and this may have led to heterogeneity in the study population and recall bias in retrospective studies. 41 Second, with the main outcome of PPSP occurrence as a categorical variable, it is also possible that we missed certain constructs of PPSP as captured by multidimensional or descriptive tools, such as PROMs 66 after hip and knee arthroplasty which has been well described elsewhere. 40,44,61,117,124,130 Third, this review included data both from studies on THR and TKR, although the literature has shown that pain and patient satisfaction outcomes from THR are generally better in comparison with TKR. 64 However, we analyzed the data separately, where possible. Fourth, we could not account for the effect of pharmacological and nonpharmacological interventions on the reporting of pain from the available data. For example, there were several predictor variables reported as important in the individual studies, but for which not enough data were available to conduct a meaningful metaanalysis. These include coping skills, negative beliefs about opioids having a higher PPSP risk, 22 biomechanical factors, and QST measures. These factors were qualitatively summarized based on multivariate analyses in some studies but require further and more rigorous evaluation, ideally in the setting of multicenter studies. Several of the included studies described perioperative interventions that were available only from 1 study. 14,18,115,128,19,21,36,51,76,86,88,96 We did not exclude them and summarized their findings qualitatively; however, the ability to draw generalizable conclusions from these studies remains limited. Fifth, there was also marked heterogeneity in the study designs, interventions (eg, spinal anesthesia may offer shorter duration of analgesia compared with continuous epidural analgesia 31 ), statistical analyses undertaken, and ROB scores. THA or TKA may be performed under general, regional, or neuraxial anesthesia (or a combination of these); the choice may be based on institutional practices, patient comorbidities, and patient preference. 28 In this review, 4 articles focused on regional anesthesia 14,51,76,128 and 2 on intrathecal analgesia. 96,115 ; however, with insufficient information to draw conclusions on differences in anesthetic approaches in the context of PPSP prevention. Finally, the follow-up periods were grouped to a mean of 6 months postoperatively (as per inclusion criteria) so some precision may be lost in the meta-analyses. As no widely available risk of the bias assessment system is available for a group of studies with mixed designs, we used previously published tools to adapt to the needs of this review; it has been used in reviews with similar methodology 56 ; however, the entire battery of questions has not been validated as a single tool.

Conclusions
Our review systematically addressed factors associated with risk for PPSP and identified that higher preoperative state anxiety and depression increase the risk of PPSP after TKR. No consistent risk factors for PPSP after THR were identified in the metaanalysis. In the qualitative summary of multivariable analyses performed in individual studies, higher preoperative pain scores and more severe acute postoperative pain were associated with a higher risk of PPSP after TKR or THR. There was a wide variation in the methods of pain assessment and in the tools used to collect perioperative variables. Standardization of tools and methods for perioperative data collection and PPSP assessment, Qualitative summary of risk factors for PPSP reported in multivariable analyses in included studies.
Results are color coded for the type of associations. Red, increased odds of PPSP; Green, decreased odds of PPSP; Yellow, no association with PPSP; White, not reported. improvement in follow-up rates, proper characterization of patients who dropped off from the studies, and ascertaining the reproducibility of PPSP prevention strategies by conducting multicenter studies can all improve the understanding and mitigation strategies of PPSP after joint replacement surgeries.

Disclosures
S. Haroutounian reports research grants from Disarm Therapeutics and personal fees from Rafa Laboratories and Vertex Pharmaceuticals, outside the scope of this paper. The remaining authors have no conflicts of interest to declare.